Apparatus for altering composition of nutritional product during enteral tube feeding

ABSTRACT

An apparatus is disclosed for modifying a liquid enteral nutritional product during delivery thereof from a supply thereof, such as a hangable container, to a feeding tube delivering the liquid enteral nutritional product to the gastrointestinal tract of a patient. The apparatus has at least one formulation chamber, such as a drip chamber, with at least one controlled release dosage form unit in the form of a coated tablet, osmotically driven device, coated capsule, microencapsulated microspheres, agglomerated molecular sieving type material, or a quantity of fine hollow permeable fibers located therein. The controlled release dosage form unit or units contain at least one beneficial agent selected from nutrients, medicaments, probiotics, or diagnostic agents or mixtures thereof, to any of which a physiologically acceptable marker dye in controlled release dosage form and/or the same or different beneficial agent not in controlled release dosage form may be added. A liquid nutritional product flows through the formulation chamber during enteral tube feeding of a patient.

FIELD OF THE INVENTION

The invention relates to an apparatus for feeding liquid enteralnutritional products and particularly to modifying a liquid enteralnutritional product having a viscosity in the range of from 1 to about300 centipoises (cps.) by adding ingredients during the feeding thereofinto the gastrointestinal tract of a patient.

BACKGROUND OF THE INVENTION

The feeding of a liquid enteral nutritional product from a hangablecontainer, such as a bottle or a plastic bag with a bottom outletconnecting to a drip chamber and the latter to a flexible tubing, orlumen, leading to a nasogastric tube or a feeding tube inserted througha gastrostomy or a jejunostomy, by gravity flow or aided by a pump, iswell known. The liquid enteral nutritional product may be asepticallyprocessed or terminally retorted, and may be supplied in a pre-filled,ready-to-hang container, or placed in such a container by a caregiver.However, the selection of diets, particularly special diets, fromamongst the rather modest number of typically available liquid enteralnutritional products is limited. This narrows, as a practical matter,the choices of the attending physician as to diet modifications,temporary or long term, that might significantly benefit the patient. Inview of the now-recognized importance of providing aseptic nutritionalcompositions, it can be seen that modified diets are not easily preparedwithout observing the stringent requirements needed to deliver anaseptic nutritional composition to the patient. The need to observe suchrequirements has heretofore militated against preparing small quantitiesof special diets designed for a specific patient.

Moreover, a number of nutrients as well as medicaments, diagnosticagents, and other ingredients such as probiotics, that at any given timemight be desirable to orally administer to a patient are not stableduring heat sterilization or may not be mutually compatible with otherdesired ingredients for an extended period of time, such as days or evenmonths until used, and thus are not readily amenable to large scalepreparation and consequent storage as the product moves throughcommerce.

Drug delivery systems have been described and claimed in U.S. Pat. Nos.4,511,353, 5,318,558 and 5,324,280 in which the drug component to bedelivered is stored in a capsule from which it is ejected over time uponosmotic infusion of moisture into the capsule, the drug being carriedaway from the outside surface of the capsule by a suitable liquid in anintravenous, i.e., parenteral, delivery system, or even, by the deviceof U.S. Pat. No. 5,318,558, by body fluids upon implantation of thecapsule.

In U.S. Pat. No. 5,069,671 there is described a formulation chamber,which may also be a drip chamber, in which various forms of sustainedrelease mechanisms are employed to release a drug or medicament, orother physiologically beneficial component such as a nutrient, withinthe formulation chamber from which the drug or other component iscarried by a suitable liquid into a parenteral delivery system.

The teachings of U.S. Pat. Nos. 4,511,353 and 5,069,671 are directed tointravenous delivery of parenteral compositions, and in the case of thelatter patent, includes delivery by infusion through intravenous,intraarterial, intraperitoneal or subcutaneous routes. The osmoticdosage system of U.S. Pat. No. 5,324,280 is concerned with the deliveryof drug formulations over time to a biological environment, such as atissue or organ implant in a mammal, or a stream or tank for marinelife. The osmotically driven device of U.S. Pat. No. 5,318,558 is saidto be usable to deliver drugs, medicaments and nutrients in a range ofenvironments extending from veterinary medicine to human drugadministrations, and to hobby situations such as fish tanks. Again, inthe case of human administration, the delivery appears to be within atissue or organ implant.

Although the osmotic delivery devices and other forms of sustained orcontrolled release dosage forms or reservoirs have been known for sometime, so far as is known, there has been no attempt to utilize such adelivery system to add one or more nutrients, or one or moremedicaments, or a mixture of nutrients and medicaments, or a probiotic,or a diagnostic agent, or any of these in admixture with a marker dye,to a liquid enteral nutritional product, with a viscosity up to 300cps., during the administration of the nutritional product to thegastrointestinal tract of a patient. Liquid enteral nutritional productscurrently on the market are described in the reference text "NutritionIn Critical Care", Gary P. Zaloga, ed., Mosby--Year Book Inc., St.Louis, Mo., 1994, at Chapter 24, authored by Barbara Hopkins, Part III,"Feeding", pp. 439-467. This reference indicates that complete nutrientcompositions contain proteins, carbohydrates, fibers, fats, and vitaminsand minerals in various proportions in an aqueous or aqueous/fat medium.Nutrient compositions for special diets may omit one or more classes ofthese components.

SUMMARY OF THE INVENTION

A first aspect of the invention concerns an apparatus for addingingredients to a liquid enteral nutritional product during delivery ofthe nutritional product from a supply thereof, such as a hangablecontainer, to a feeding tube delivering the nutritional product to thegastrointestinal tract of a patient.

The apparatus comprises:

a formulation chamber, usually in the form of a drip chamber,connectable to a supply container of a liquid enteral nutritionalproduct, normally an aqueous composition, the formulation chamber havingan inlet and an outlet,

at least one beneficial agent in controlled release dosage form, eachcontrolled release dosage form unit being disposed in the formulationchamber so as to be wetted by or immersed in the liquid enteralnutritional product traversing the formulation chamber, and eachbeneficial agent being dispersible in the medium of the liquid enteralnutritional product, and

fluid communication means connecting the outlet of the formulationchamber to a tube for feeding the modified enteral nutritional product,containing the so-added at least one beneficial agent, into thegastrointestinal tract of a patient.

Each at least one beneficial agent that is to be added in controlledrelease dosage form during feeding is added in at least aphysiologically effective or diagnostically detectable amount and isselected from the group consisting of: a nutritional ingredient; amedicament ingredient; a chemically and physiologically compatiblemixture of: a plurality of nutritional ingredients, or a plurality ofmedicament ingredients, or at least one nutritional ingredient and atleast one medicament ingredient; a probiotic; or a diagnostic agent;and, any of the foregoing ingredients or mixtures of ingredients inadmixture with at least one physiologically acceptable, and ingredientcompatible, marker dye or dye mixture that is dispersible in the mediumof the liquid enteral nutritional product.

The formulation chamber may be a conventional drip chamber which hereserves also as the formulation or contact chamber. The formulationchamber may be provided, in addition to the controlled release dosageform or forms therein, and whether or not marker dye is employed, withthe same or different beneficial agent or agents not in controlledrelease dosage form, if desired, in order to add greater amounts ofsuch, or to add a beneficial agent as a bolus. Further, the marker dyeor dyes may be provided separately from the beneficial agents, in theformulation chamber, in one or more controlled release dosage forms.

If desired, one or more additional contact or formulation chambers maybe employed, either in series or in parallel, but feeding into one fluidcommunication means leading to the feeding tube of a patient. Whereinmore than one formulation chamber is used, at least one formulationchamber will have positioned therein at least one controlled releasedosage form containing at least a useful or detectable amount of atleast one beneficial agent as above defined, while each additionalformulation chamber may contain one or more beneficial agents in eitheror both controlled release and non-controlled release dosage forms. Theuse of more than one formulation chamber facilitates the addition ofingredients not readily available in combination or not compatibleduring storage together in a controlled release dosage form.

In each formulation chamber the beneficial agent or agents, whether incontrolled release dosage form or not, are positioned, and held orsupported, if necessary, so that the liquid enteral nutritional productbeing modified contacts and wets or immerses the dosage form of thebeneficial agent or agents therein. Preferably, each controlled releasedosage form is shaped or held in such a manner as to prevent or avoidthe beneficial agent blocking flow of the liquid enteral nutritionalproduct out of the drip chamber or formulation chamber in which it ispositioned.

The combination of (1) a formulation chamber, ordinarily in the form ofa drip chamber, and (2) fluid communication means, accompanied by (3) atleast one beneficial agent, as herein defined, in controlled releasedosage form disposed in the formulation chamber, or, merely accompanyingthe formulation chamber, in either case when the three parts aresupplied together, constitutes a useful kit for evacuating a liquidenteral nutritional product from a supply container, such as a hangablecontainer, and modifying the liquid enteral nutritional product byadding one or more beneficial agents thereto as it is flowing from thecontainer and feeding the modified product into the gastrointestinaltract of a patient. The formulation chamber of the kit may also beloaded with or be accompanied by a marker dye or dyes in a separatecontrolled release dosage form and/or one or more beneficial agents in asuitable non-controlled dosage release form, for example, in uncoatedparticulate or tablet form in a porous carrier envelope such as a teabag-like packet. The marker dye or dyes may be of types visible undereither or both white light or ultraviolet light. Preferably, the atleast one beneficial agent in controlled release dosage form and anyother additives in non-controlled release dosage forms supplied as partof a kit are already positioned in the formulation, or drip, chamber. Ifnot, they are readily manually placed in the formulation chamber,ordinarily prior to connecting the apparatus to the supply containerfrom which the liquid enteral nutritional product is to be evacuated.

In a further aspect of the invention, the invention concerns a method ofpreparing a special liquid diet for enterally feeding a tube fed patientcomprising modifying a liquid enteral nutritional product during theflow thereof from a supply container containing such composition to afeeding tube leading into the gastrointestinal tract of the patient.More specifically, the method comprises the steps of:

A. providing an apparatus comprising:

(a) a formulation chamber having an inlet and an outlet, the inlet beingconnected in fluid communication to the supply container of the liquidenteral nutritional product,

(b) a physiologically effective or diagnostically detectable amount ofat least one beneficial agent in controlled release dosage form, eachbeneficial agent being disposed in the formulation chamber so that thedosage form thereof is contacted by or immersed in the liquid enteralnutritional product traversing therethrough, each beneficial agent beingdispersible in the medium of the liquid enteral nutritional product andeach beneficial agent in controlled release dosage form being selectedfrom the group consisting of: a nutritional ingredient; a medicamentingredient; a chemically and physiologically compatible combination of:a plurality of nutritional ingredients, or a plurality of medicamentingredients, or at least one nutritional ingredient and at least onemedicament ingredient; or a probiotic ingredient; or a diagnostic agent;and, any of the foregoing ingredients or combinations of ingredientstogether with at least one compatible, physiologically acceptable,marker dye that is dispersible in the medium of the liquid enteralnutritional product, and

(c) fluid communication means capable of operatively connecting theoutlet of the formulation chamber to a tube for feeding a liquid enteralnutritional product into the gastrointestinal tract of the patient;

B. providing a supply container containing a liquid enteral nutritionalproduct;

C. placing the apparatus in communicative series in the fluid flowbetween the supply container and the feeding tube; and,

D. flowing the liquid enteral nutritional product through the apparatuswherein the product becomes modified and into the feeding tube.

In a modification of this method which may be especially useful intailor-making a diet for a patient, one or more beneficial agents thatare not in controlled release dosage form are added to the formulationchamber. The added beneficial agent or agents may be the same ordifferent than the specific beneficial agent or agents provided in theformulation chamber in controlled release dosage form. The addedbeneficial agents which are not in controlled dosage form are added toaccomplish a bolus feeding or bolus effect, or, simply to add a greateramount of a given beneficial agent. Also, marker dye in a separatecontrolled release dosage form, which may be surface coated with readilysoluble dye to impart quick initial dye marking, may be added to theformulation chamber. In another modification the fluid communicationmeans is provided with one or more additional formulation, or contact,chambers, that are not necessarily drip chambers, but which each havepositioned therein either a marker dye, or, a beneficial agent, asherein defined, in controlled or non-controlled release form, or acombination of marker dye and beneficial agent. The formulation chambersare connected to a supply of liquid enteral nutritional product andpositioned so as to permit the flow of the liquid enteral nutritionalproduct over each dosage form therein to contact it or even immerse itdynamically, i.e., immerse it in a quantity of liquid that constantlyturns over, in order to take up the beneficial agent and/or dye contentand convey such to a feeding tube of a patient. A pump may be used, ifneeded or desired, to flow or help flow the modified liquid enteralnutritional product into the feeding device or tube.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be better understood with reference to theappended drawings in which:

FIG. 1 is a partly schematic representation of an apparatus formodification of a liquid enteral nutritional product and tube feeding itnasogastrically according to the invention;

FIG. 2 is a partly schematic representation of an apparatus formodification of a liquid enteral nutritional product and tube feeding itvia a gastrostomy tube according to the invention;

FIG. 3 is a partly schematic representation of an apparatus formodification of a liquid enteral nutritional product and tube feedingit, with the aid of a pump, via a jejunostomy tube according to theinvention;

FIG. 4 is an enlarged fragmentary view in front elevation of the lowerportion of a hanging supply container of a liquid enteral nutritionalproduct, such as the container shown in FIGS. 1 to 3, with the beveledinlet tube of a drip chamber inserted through the closure and dependingtherefrom and with a beneficial agent in controlled release dosage formdisposed inside the drip chamber and immersed in the flowing liquidenteral nutritional product, the lower part of the drip chamber and thecontrolled release dosage form within being partly broken away and insection, and the tubing portion of the fluid communicating means, i.e.,primarily the tubing leading away from the drip chamber, being truncatedfor purposes of illustration;

FIG. 5 is a perspective view of a drip chamber usable according to theinvention with a controlled release dosage form in the shape of asubstantially rectangular solid with slightly rounded corners disposedwithin the drip chamber, the beveled inlet tube end of the drip chamberbeing the upper end that is thrust in the normal manner through theclosure of the supply container to communicate therewith and receiveliquid enteral nutritional product therefrom;

FIG. 6 is a perspective view of the drip chamber of FIG. 5 inverted toshow more of the detail of construction;

FIG. 7 is a perspective view, partly broken away and in section, of arectangular solid-shaped controlled release dosage form, of the osmoticpump type, used to supply a beneficial ingredient or mixture thereofwithin the formulation chamber according to the invention;

FIG. 8 is a view in front elevation, partly broken away and in section,of a nearly rectangular solid-shaped controlled release dosage form, ofanother osmotic device type, used to supply a beneficial ingredient ormixture thereof within the formulation chamber according to theinvention;

FIG. 8A is a view similar to FIG. 8 of a sustained release dosage formof the same type but with an external coating of marker dye that isreadily taken up immediately in the medium of the liquid enteralnutritional product at the outset of commencing flow through theformulation chamber and of use wherein the dosage form contains markerdye for the sustained release thereof;

FIG. 9 is a view in front elevation, partly broken away and in section,of a nearly rectangular solid-shaped carrier of controlled releasedosage forms, of the microencapsulated particle type or molecularsieving type, used to supply a beneficial ingredient or mixture thereofwithin the drip chamber according to the invention;

FIG. 9A is a perspective view, partly broken away and in section, of ahighly permeable fibrous packet, preferably of the non-woven teabag-type of carrier, suitable for placing in a drip chamber, or otherformulation chamber, and capable of holding a sustained release dosageform, such as a coated tablet, or an osmotic delivery device, or acoated capsule, or a capsule containing a quantity of controlled releasedosage forms in the form of microencapsulated particles or molecularsieving type material or permeable hollow fibers, each such dosage formarticle or unit containing at least one beneficial agent or a mixturethereof with marker dye. A beneficial agent not in controlled releasedosage form, whether tabletted or agglomerated or loose particulate,also may be placed in measured amount in a porous carrier such as one ormore fibrous packets of the sort shown in FIG. 9A and used in aformulation chamber in addition to one or more controlled release dosageform units or separately if there is at least one such controlledrelease dosage form placed in the same formulation chamber or in atleast one formulation chamber used with the same communication means. Asmall quantity of marker dye not in controlled release dosage form mayalso be placed in the fibrous packet for quick initial dye marking;

FIG. 10 is a view in side elevation and partly truncated, of a feedingset, or kit, including a beneficial agent in controlled release dosageform to be placed in the formulation chamber by the caregiver, the kitbeing useful in modifying a liquid enteral nutritional compositionduring the feeding thereof according to the invention;

FIG. 11 is a view similar to FIG. 4, but with the controlled releasedosage forms of any of FIGS. 7 to 9A confined within a mesh sleeve orbag;

FIG. 12 is a view similar to FIG. 4, but with the controlled releasedosage forms of any of FIGS. 7 to 9A confined within a foraminated,pierced, or fibrous sleeve or bag;

FIG. 13 is a view similar to FIG. 4, but with a plurality of thecontrolled release dosage forms of any of FIGS. 7 to 9A supported by aforaminous plate above the bottom orifice of the drip chamber;

FIG. 13A is a view in transverse section of a formulation chamber takenat the level just above a grid that has been placed in the drip chamberof FIG. 13 in place of the foraminous plate there shown for the supportof a controlled release dosage form positioned in the drip chamber;

FIG. 14 is a view in side elevation similar to FIG. 13 showing a dripchamber depending from a supply container with liquid enteralnutritional product flowing through the chamber over a beneficial agentin a controlled release dosage form intermingled with added beneficialagent not in controlled dosage form while the dosage forms are supportedon a perforated plate near the bottom of the formulation chamber;

FIG. 15 is a side elevation of a feeding set according to the invention,including a drip chamber, loaded with a beneficial agent in controlledrelease dosage form, and fluid communication means to connect the dripchamber with the feeding tube used to direct the modified liquid enteralnutritional product to the gastrointestinal tract of a patient,including a protective removable cap for the end connector;

FIG. 16 is a view in side elevation of a feeding kit in which a secondformulation chamber has been attached by its inlet in fluidcommunication to the end of the flexible tubing that normally attachesto a fitting that connects to the feeding tube of the patient, theoutlet tube of the formulation chamber having a fitting for connectionto the feeding tube;

FIG. 17 is a perspective view of a suitable formulation chamber similarto that shown in FIG. 5 but with a different form of attachment forconnection to a supply container, the cap here is threadably attached toa supply container and is integrally formed with the top of theformulation chamber;

FIG. 18 is a perspective view of the formulation chamber shown in FIG.17 as viewed in the opposite direction;

FIG. 19 is a side elevation of a feeding set in which two formulationchambers are connected in series, here in tandem; and

FIG. 20 is a view in side elevation of part of the apparatus formodifying a liquid enteral nutritional product during enteral feedingwherein two formulation chambers are suspended from respective hangingsupply containers, each containing liquid enteral nutritional product,the outlets of the formulation chambers being connected to tubingsegments that connect to a "Y" fitting that joins the parallel flow fromeach formulation chamber into a single stream within the communicationmeans, here truncated.

DEFINITIONS USED HEREIN

The following terms and phrases are defined for the purposes of thedescription and claims.

"Enteral" nutritional products refers to liquid compositions commonlyunderstood to be supplied to and utilized in the gastrointestinal tractsof patients. Such enteral nutritional products have a viscosity in therange of 1 to about 300 cps. and most frequently in the range of about 5to about 150 cps.

"Enteral nutritional product medium" refers to the liquid portion of aliquid enteral nutritional product, mainly water, but often includinglesser or minor amounts of one or more liquid non-aqueous substancessuch as lipids, e.g., vegetable oil and marine oil.

The term "gastrointestinal tract" as used herein refers only to thestomach and the small bowel. Feeding to the gastrointestinal tract isdone by use of a nasogastric tube extending through a nasal passage andthe esophagus and thence to the stomach, or by use of a feeding tubeextending through the abdominal wall to the stomach or small intestine.

A "physiologically significant" or "beneficial" ingredient is aningredient that is, or is believed to be, nutritionally orpharmaceutically important to the patient, or is otherwise medicallyimportant as in the case of a probiotic, or, a diagnostic agent such asan opaquing agent.

A "probiotic" is understood to be a live microbial food supplement whichbeneficially affects the human host by improving the individual'smicrobial balance in the gastrointestinal tract, e.g., Lactobacillusreuteri.

A "beneficial agent or ingredient that is dispersible in the medium ofthe liquid enteral nutritional product" is an agent or ingredient thatis physiologically beneficially added, or otherwise usefullybeneficially added, as in the case of a diagnostic agent, to the liquidnutritional product during enteral feeding, and is dispersible in themedium of the nutritional product. The beneficial agent(s) oringredient(s), whether or not supplied by, i.e., from, controlledrelease dosage form units or devices, and used according to theinvention, must be dispersible in the medium of the liquid enteralnutritional product being modified during feeding, in order to becarried along with the nutritional product into the gastrointestinaltract of the patient.

A "useful amount" of a beneficial ingredient that is dispersible in themedium of the liquid enteral nutritional product is an amount that is"physiologically effective or diagnostically detectable" with respect toa patient, i.e., it produces, or is reasonably expected to produce, adetectable beneficial effect on the patient on either a short term orlong term basis when fed as part of a liquid enteral nutritionalproduct, or, is detectable in diagnosing a condition or disease.Generally not more than about 5 grams of beneficial agent will becontained in a single controlled release dosage form unit or device, anda plurality or even multiplicity of units such as microencapsulatedmicrospheres containing a given beneficial agent may be employed toprovide a desired level of the beneficial agent in the nutritionalproduct being fed.

The phrase "at least one beneficial agent dispersible in the medium ofthe liquid enteral nutritional product" is meant to refer to thesingular as well as the plural, as may well be adjudged from thecontext, and includes combinations of ingredients, agents or factors.

The term "dispersible" as used herein with respect to beneficialagent(s) or ingredient(s) is to be understood to apply to substancesthat are soluble as well as those that are suspendable enough to betaken up readily and carried along by the liquid medium as the liquidenteral nutritional product flows through the formulation chambercontaining the one or more controlled release dosage forms.

The term "feeding set" refers to the combination of a drip chamber, orother formulation chamber, and fluid communication means leading to afeeding tube for enteral feeding. The drip chamber or other formulationchamber is loaded with or accompanied by at least a useful amount of atleast one beneficial agent in controlled release dosage form, thebeneficial agent being as above defined with or without a marker dye incombination and with or without additional beneficial agent that is notin controlled release dosage form. The term also encompasses such afeeding set having at least one additional drip chamber or one or moreformulation chambers in fluid flow series or in parallel, as a part ofthe fluid communication means, each feeding set having at least one dripchamber or formulation chamber loaded with at least one beneficial agentin controlled release dosage form, each beneficial agent being presentin at least a useful amount as above defined. Where more than oneformulation chamber is employed, the additional chamber or chambers maycontain: (1) one or more beneficial agents in controlled release dosageform only, with or without marker dye in controlled release dosage form;or (2) one or more beneficial agents in controlled release dosage formintermingled with one or more beneficial agents not in controlledrelease dosage form, and with or without marker dye in controlledrelease dosage form; or (3) one or more beneficial agents none of whichare in controlled release dosage form, and with or without marker dye incontrolled release dosage form.

The process of "infusion" is meant to refer, in the present context, tothe process of supplying an enteral-soluble beneficial ingredient to thegastrointestinal tract of a patient extending over time from at least aminute to about 30 hours, but more usually at least about 2 hours toabout 24 hours.

The term "delivery means" denotes generically a means or system forstoring and subsequently delivering or releasing a beneficial ingredientor agent or mixture thereof within a formulation chamber such as a dripchamber during, and as a consequence of, the flow therethrough of aliquid enteral nutritional product utilizing a controlled release dosageform of the beneficial ingredient or agent.

The term "a controlled release dosage form" refers to any of the wellknown conventional controlled release forms, such as a coated tablet,osmotic delivery device, coated capsule, microencapsulated particlessuch as microspheres, agglomerated particles, e.g., molecular sieveparticles, or a fine, hollow, permeable-walled fiber as a bundle ofchopped fibers or a coil, each a form that contains and stores andsubsequently releases, or disperses in the case of the osmoticallydriven devices, a useful content of a beneficial agent into the mediumof a liquid enteral nutritional product at room temperature in a slow,or delayed or intermittent manner as compared to the solubilitycharacteristics normally exhibited by that beneficial agent, when inuncoated or untreated particulate form, in the said medium at about roomtemperature. Any dosage form which employs coating, encapsulation,microencapsulation, enclosure in an osmotically driven device, orcapture in a molecular sieving type structure or in a permeable finehollow fiber, to retard or slow down, delay or intermittently delaysolubilization of a promptly soluble beneficial agent so that itsdissolution, or disperson as with an osmotically driven device, takesplace during the course of at least 30 minutes, and preferably at leasttwo hours, of contact by flowing liquid enteral nutritional product, or,the release is delayed, i.e., not commenced, for at least 10 minutesafter initial contact in a formulation chamber by the liquid enteralnutritional product, is exhibiting controlled release behavior. As to abeneficial agent that is inherently not promptly soluble in the mediumof a liquid enteral nutritional product, any such dosage forms thatretard or slow down, delay or intermittently delay solubilization ofsuch a beneficial agent by at least 20 percent of the normal time forsolubilization or dispersion into the medium of a liquid enteralnutritional product, of a given unit amount of the beneficial agent thatis not coated or treated to obtain a controlled release is consideredfor the purposes of the description and claims to be a controlledrelease dosage form. Preferably, the controlled release dosage formsprolong release of the contents thereof for a time appropriate to thenutrient or medicament or other beneficial agent being supplied.

On the other hand, merely tableting a beneficial agent either unmixedwith another material, or not admixed with a relatively insoluble bindertype excipient, for example, while resulting in a smaller surface areabeing exposed to a solvent liquid and a slower dissolution rate thanthat of a fine particulate form of the beneficial agent, is not to beconsidered making the beneficial agent into a controlled release dosageform. Clearly, a beneficial agent in a particulate form that has notbeen coated with or enclosed in any other material is not in controlledrelease dosage form. Nor are uncoated tablets or particles of abeneficial agent, clearly not in controlled release dosage form, to beconsidered transformed into controlled release form merely by beingenclosed in a carrier such as a fibrous tea bag type of packet or aneasily dissolved or disintegrated capsule.

The "controlled release dosage forms" useful according to the inventionare understood to include delayed or intermittent release as well assustained release dosage forms, some of which constitute "ratecontrolling means" or "rate controlled dosage forms". Preferably, thecontrolled release dosage forms prolong release of the contents thereoffor a time appropriate to the nutrient or medicament being supplied.

The terms "controlled release dosage form units" or "controlled releasedosage form particles" are to be understood to refer to individualcoated tablets or coated capsules or devices such as osmotic deliverydevices or microcapsule particles or small bundles of fine hollow fibersor small agglomerated clumps of molecular sieving type material, eachcapable of the sustained delivery or delayed or intermittent delivery ofbeneficial agent or marker dye as defined above.

It should also be understood that the phrase "flowing the liquid enteralnutritional product through the apparatus, wherein it becomes modified,and into the feeding tube" is meant to include utilizing gravity flowfrom a hanging container, as well as using a pump in addition to orwithout gravity flow to promote the flow of the modified liquid enteralnutritional product into and through a feeding tube.

DETAILED DESCRIPTION OF THE INVENTION

Referring now to the drawings in which like parts are referred to bylike reference numerals, the apparatus of the invention is shown in FIG.1 in the form of a feeding set, indicated generally by the numeral 20,connecting the outlet 21 of the hanging supply container 22 to thenasogastric feeding tube 23 that extends through a nasal passage 24 ofthe patient and down the esophagus 25 to the stomach 26. The feeding sethere consists of a formulation chamber 27, in the form of a drip chamberthat serves also as a contact or formulation chamber, and fluidcommunication means indicated generally by the numeral 28.

"Fluid communication means" is to be understood to include allcomponents of fluid communication utilized in series from the dripchamber outlet 29 to the connection 30 to the feeding tube, such as thenasogastric feeding tube 23. Components include not only portions offlexible tubing 54 but also any additional drip chambers or otherformulation chambers connected in series as seen in FIGS. 16 and 19 forseries flow, or in parallel but soon joined into a single stream as seenin FIG. 20, for flow of the liquid enteral nutritional product to thefeeding tube of the patient. The components may also include any specialtubing portions needed for utilization of a pump, and, connectorelements, respectively, between all the other components, such asconnector elements 31 or adapters 30.

It may be helpful to utilize two formulation chambers in tandem, such asdrip chambers 27 and 73 as seen in FIG. 19, to introduce a greaterconcentration or amount of a given ingredient. The formulation chambersmay be used in tandem also to introduce different respective beneficialingredients that are not supplied together within the same controlledrelease dosage form unit or particle. The respective ingredients mayconstitute a little-used combination, for example, or they may not becompatible in storage together within a controlled release reservoir.

Two formulation chambers are shown in use sequentially in series in thefeeding set of FIG. 16 wherein the second formulation chamber 76 isattached at the end of the flexible tubing 54 which is distal from thesupply container. This may be found useful for adding a specialbeneficial ingredient to a feeding set already made up. With theformulation chamber 76 at the end of the set which is distal from thesupply container, it will most likely be positioned horizontally asdepicted, and is preferably made with a bulbous mid-portion 77 or a lowlying longitudinal channel portion wherein the beneficial agent 32 incontrolled release dosage form will lie at the lower side of theformulation chamber and be wetted by the flowing liquid enteralnutritional product. If the beneficial agent is not in controlled dosageform it will likewise lie, for example, at the lower side of the bulboussection 77 until dispersed.

Dual formulation chambers 74 may be used in parallel as indicated inFIG. 20, and for the same reason as the tandem chambers, or, it may besimpler wherein it is desired to feed one beneficial agent on a bolusbasis and another on a sustained basis. It is preferable to hang suchchambers from respective supply containers, as shown, to avoid problemsof control in order to get adequate flow through both formulationchambers from a single supply container, which would preferably requirethe use of a splitter valve to apportion intake flow between the twoparallel routes. The outlets of each formulation chamber shown in FIG.20 are connected to segments of flexible tubing 54 that lead to a "Y"fitting 75 in which the streams of liquid enteral nutritional productare joined.

Referring again to FIG. 1, the formulation chamber 27 has positionedtherein a controlled release dosage form unit 32 containing at least aphysiologically effective or diagnostically detectable amount of atleast one beneficial ingredient that is dispersible in the medium of theliquid enteral nutritional product 33 flowing from the supply container22 into the formulation chamber 27 where the liquid enteral nutritionalproduct, which is normally water-based, contacts the controlled releasedosage form unit 32, wetting it or immersing it within the formulationchamber 27, causing the release or discharge into the nutritionalcomposition of the dispersible beneficial ingredient or ingredients, inaddition to marker dye if included, stored in the reservoir. The flow ofliquid enteral nutritional product is conveniently started or shut offor sometimes regulated by the use of a conventional adjustablecompression clip 34.

Turning now to FIG. 2, a hanging supply container 22 is shown supplyingliquid enteral nutritional product 33 to a formulation chamber 27 fromwhich the liquid enteral nutritional product flows through flexibletubing 54 of the feeding set 20a to the gastrostomy feeding tube 23a.The gastrostomy feeding tube shown in FIG. 3 is merely exemplary of thelarge variety of gastrostomy feeding tubes which are commerciallyavailable, it being understood that the apparatus of the presentinvention is usable with a variety of gastrostomy feeding tubes.

In FIG. 3 there is shown a feeding arrangement for a jejunostomy muchlike the apparatus in FIG. 1, except that the feeding set 20b is adaptedto be used with a pump 35 which provides positive flow into a feedingtube 23b leading to the small bowel 26a of the patient, whereas in anumber of cases gravity flow is utilized. Also, a second formulationchamber 27a is employed as part of the feeding set 20b in order to addadditional or different beneficial agent and/or marker dye, eachdispersible in the medium of the liquid enteral nutritional product 33flowing from the supply container 22 to formulation chamber 27 andthence through the rest of the communication means 28b and formulationchamber 27a of feeding set 20b to the jejunostomy feeding tube 23b. Theadditional beneficial agent may be in controlled or noncontrolled dosageform.

If desired, or needed, as often is the case when feeding via a feedingtube, such as a jejunostomy tube, a pump, such as a peristaltic pumpwith cam action acting upon the flexible tube portion 54 of thecommunication means 28, or a positive displacement pump with adisposable fluid infusion pumping chamber cassette such as thatdescribed in U.S. Pat. No. 4,927,411, and connected in series in thecommunication means, may be used to flow or help flow the modifiedliquid enteral nutritional product into the feeding tube, for example,when it is not convenient to hang or otherwise locate the supplycontainer in an elevated position relative to the patient, or, when thenutritional product is rather viscous and flows slowly by gravity flow.The fluid communication means 28 of the apparatus utilized willordinarily include a flexible tubing portion 54 connectable to or usablewith a conventional pump. If the pump employed, for example, is aperistaltic pump that requires especially shaped flexible tubing, suchtubing may be substituted for all or a part of the communication meansdelivering modified nutritional product from the formulation chamber tothe feeding tube of the patient.

The end of the flexible tubing 54 connected to the inlet end of secondformulation chamber 27a is preferably provided with a coupling element30 such as that shown in the feeding set in FIG. 15, while the inlet endof the formulation chamber is shaped complementarily to receive thecoupling element, and the outlet of the formulation chamber communicateswith a short length of flexible tubing which likewise terminates in acoupling element 30, that is connected to the feeding tube 23b. It maybe seen that it is convenient to add the second formulation chamber 27a,when the need arises, without having to disconnect the parts of thefeeding set. Here, for example, the flexible tubing 54 would have to bedisconnected from the drip chamber 27 to add the formulation chamber 27adirectly in tandem at that end of the set.

The formulation chamber 27 has been loaded with a beneficial agent incontrolled release dosage form 32, while the second formulation chamber27a has been provided with the same or a different beneficial agent notin controlled release dosage form. The use of beneficial agent not incontrolled release dosage form is illustrated also in FIG. 14 where aplurality of sustained release dosage form units 32 containingbeneficial agent(s) are supported above the pierced plate 53 along withbeneficial agent not in controlled release dosage form as particles ordispersible tablets 80.

The formulation chamber 27a may be hung vertically, like a conventionaldrip chamber, but will probably be more conveniently positioned with thedirection of flow of the liquid enteral nutritional product therethroughapproximately horizontal. Consequently, the formulation chamber 27ashould be provided with means to guide or channel the liquid nutritionalproduct to physically contact the controlled release dosage form unit orunits therein. Such means may be a low lying longitudinal channel in thebody wall or a bulbous enlargement of the chamber body of the sortillustrated in FIG. 16 or even a simple lateral depression in thesidewall of the lower side of the chamber, or, a trap, or weir, or anyother means to retain the dosage form units where there will be anadequate flow or depth of liquid sufficient to afford good contact withthe controlled release dosage form units or particles located in suchguide or channel means. As seen in FIG. 16, a feeding kit has beenprovided with a second formulation chamber 76 with a bulbous bodyportion 77 in which a controlled release dosage form unit 32 ispositioned so that flow of liquid enteral nutritional product willsteadily contact the controlled release dosage form unit 32 and take upbeneficial agent therefrom.

In the enlarged fragmentary view in FIG. 4, a controlled release dosageform unit 32a in the form of an osmotic device capsule is seen immersedin a liquid enteral nutritional composition 33 within the drip chamber27. This kind of controlled release dosage form unit 32a, which has anouter coating or membrane that does not disintegrate readily, shouldhave, preferably, a geometric shape, for example, that of a rectangularsolid, that will avoid blocking flow of liquid enteral nutritionalproduct 33 through a circular opening such as that of the channel 40serving as the outlet of the lower part 39 of the drip chamber 27, or,other means such as a mesh sleeve may be employed to prevent suchblockage.

The details of construction of one example of a conventional dripchamber suitable for use as a formulation chamber according to theinvention are illustrated in FIGS. 5 and 6 which are greatly enlargedperspective views. The drip chamber 27 as shown has two parts. The firstpart is a hollow, nearly cylindrical chamber body 37 with an open firstend 38, which is the upper end when the drip chamber is in its normaloperative position, and a second end 39, opposite the first end, thattapers or narrows down to form an orifice 40 leading to an integrallyformed outlet tube portion 29. The chamber body 37 is preferably formedof a clear material, such as plastic or glass, to allow see-throughvisibility of the flow of the nutritional product. Usually the dripchamber is formed of a clear, somewhat flexible, autoclaveable plastic,such as a clear polyvinylchloride or polyolefin resin.

The second part of the drip chamber 27 shown is in the nature of a plug42 with a cylindrical body that has an inward end portion 43 that snuglypress fits into the inlet end 38 of the chamber body 37. Preferably theend portion 43 of the plug body 37 that extends into the chamber bodyhas a slightly reduced diameter. The edge 44, of this end portion 43,remote from the end face of the plug is raised slightly, being a littlelarger in diameter, and serves as a stop when assembling the chamberbody and the plug together. The plug body is provided with an integrallyformed fluid communication passage 45 which may take the form of anaxial borehole in a solid plug body that communicates with an inlet tubeportion 46 that projects outwardly in the axial direction from acollar-like flange 47 that extends radially from the top end 48 of theplug body. But, preferably, in order to provide a plug body with moreresiliency for easier insertion into the upper end 38 of the chamberbody 37, the fluid communication passage 45 is a concentric tube axiallylocated within and about as long as the plug body. The concentric tube45 is integrally formed with or otherwise operatively connected to theinlet tube portion 46. A short, peripheral, integrally formed flange 50that extends longitudinally from the collar-like flange 47 along a sideof the plug body may be provided, if desired, to aid in gripping theplug body when assembling the drip chamber.

The plug may be molded of a plastic such as a polyvinylchloride resin,which may be pigmented, if desired, for visibility as an aid to observeproper seating in the chamber body.

The distal or free end 49 of the inlet tube portion 46 has asufficiently sharp beveled end to facilitate puncturing the seal (notshown) in the closure 21 in the neck of a conventional hanging supplycontainer, such as supply container 22. The collar-like flange 47 servesas a stop to the insertion of the pointed inlet tube portion 46 into theclosure 21 at the neck of the supply container 22.

Other modes of construction of the formulation chamber may be employedso long as a suitable connection to the supply container is provided aswell as a see-through tubular portion wherein the rate of flow of theliquid enteral nutritional product may be observed. For example, see theformulation chamber 82 depicted in FIGS. 17 and 18 wherein the plug end83 of the formulation chamber is integrally formed with the closure 84for a conventional supply container to be threadably connected thereto.The apparatus of the invention is not to be considered limited to theinclusion of any of the drip chambers here used by way of illustration,nor is the method limited to the use thereof.

The drip chamber shown in FIGS. 5 and 6 has a controlled release dosageform unit 32 disposed therein ready for use. The controlled releasedosage form unit will be preselected according to the contents thereofto provide the additional nutrient(s) and/or medicament(s) and/orprobiotic(s) and/or diagnostic agent(s) and/or other beneficialingredient(s) selected by the care giver in charge, along with a markerdye, if desired. As used herein and in the claims, medicaments areunderstood to be substances used in therapy. The formulation chamber, orchambers, selected may contain more than one controlled releasereservoir in order to provide a combination of nutrients, or, acombination, such as nutrients and medicaments or other beneficialagents, tailored to the needs of the patient being fed. The formulationchamber may also be one provided with the same or different beneficialagent or agents both in controlled and not-controlled release dosageform in order to provide, for example, a greater amount, as in the caseof a nutrient. A non-controlled dosage form of a beneficial agent may beused to supply the beneficial agent over a shorter period of time, asmight be desired with a medicament.

The controlled release dosage form units employed will preferably be inthe form of a coated tablet, an osmotic delivery device, a coatedcapsule, a microencapsulated microsphere, an agglomerated particle,e.g., as of molecular sieving type particles, or, a fine hollowpermeable fiber bundle, or chopped hollow permeable fibers, agglomeratedor held in a fibrous packet. To avoid having a dosage form unit orparticle block the flow of the liquid enteral nutritional compositionthrough the outlet orifice 40 of the drip chamber, if the dosage formunit is one that maintains integrity of the exterior layer or coatingthereof while the ingredients leach out or are expressed out duringcontact with the liquid enteral nutritional product, it is preferredthat the dosage form unit have a geometric shape, e.g., a rectangularsolid, or a star shape, either of which will not fully block a roundpassageway. If a different type of controlled release dosage form isused which dissolves or disintegrates so the interim shape is notcontrollable, or if it leaves an insoluble skeletal structure or debris,it is preferred to confine the controlled release dosage form units in amesh-like bag within the drip chamber or other formulation chamber suchas the mesh sleeve 51 shown in FIG. 11. In FIG. 11 there is also shown aplurality of controlled release dosage form units which may be employedin order to provide additional beneficial ingredients that aredispersible in the medium of the liquid enteral nutritional product inorder to obtain a tailor-made nutrient composition for the patient. Thismay be especially helpful wherein none of the controlled release dosageforms at hand may have the exact combination of ingredients that isdesired or needed for a patient, and the combination can be made up a lacarte if there are at hand controlled release dosage form unitscontaining the various ingredient contents desired.

As seen is FIG. 12, a foraminous sleeve, or bag, that is, one withnumerous holes in it, may be used to position the controlled releasereservoir(s) in the drip chamber or other formulation chamber.

Or, turning now to FIG. 13, a plastic or ceramic or corrosion resistantmetal plate 53 that is foraminous or pierced may be placed within thebody of the lower part of the drip chamber 37, or other formulationchamber, to support the controlled release dosage form units, in thiscase, a very large number where the desired ingredient is needed inrelatively large amount. If desired, the foraminous plate 53 may bereplaced by a grid or screen 41, such as that shown in FIG. 13A and isalso preferably formed of a plastic or vitrified ceramic or corrosionresistant metal, such as stainless steel.

The foregoing means of disposing, i.e., supporting, the controlledrelease dosage form units within the drip chamber may also be used inany additional formulation chambers in the feeding set employed.

The controlled release dosage form unit depicted in FIG. 7 is of theosmotic pump type that functions in the manner of the osmotically drivendelivery device described and claimed in U.S. Pat. No. 5,318,558, thespecification and drawings of which are incorporated herein by referencewith respect to the structure of the controlled release dosage formunits therein described and the method of making them and their mode offunctioning, albeit here with different environments and contents andend uses. In the pump type controlled release dosage form units, ordelivery devices, the beneficial ingredient(s) in liquid form, i.e.,either in the liquid state or in solution in a suitable solvent, isexpressed out from a cylindrical enclosure or cavity 56 within thereservoir through a small orifice 57 by the action of a piston 58 drivenby pressure developed by osmotic infusion of moisture through asemi-permeable membrane 59 confining a hydro-active substance 60 behindthe piston 58, driving the piston steadily toward the side of thereservoir where the ingredient(s) 61 is forced out through the orifice57. Orifice 57 is very small and is preferably drilled by a laser beam.The cylindrical enclosure 56 is formed within an outer non-permeablemembrane or coating 62. The hydro-active substance 60 may be awater-soluble salt like magnesium sulfate, magnesium chloride, potassiumsulfate, sodium chloride, sorbitol, inositol, urea, or a saccharide suchas glucose or fructose or dextran, or, a hydrophilic polymer such as apoly(hydroxyalkyl methacrylate) with a molecular weight of 30,000 to5,000,000, or a poly(vinylpyrrolidine) with a molecular weight of 10,000to 360,000, an anionic or cationic hydrogel or polyvinyl alcohol havinglow acetate residual.

The controlled release reservoir depicted in FIG. 8 is another osmoticdosage system with a sustained release dosage form that functions in themanner of the osmotically operated delivery device described and claimedin U.S. Pat. No. 5,324,280, the specification and drawings of which arehereby incorporated herein by reference with respect to the structure ofthe sustained release dosage form units there described and the methodof making them and their mode of functioning, albeit here with differentenvironments and contents and end uses. In this type of system, thebeneficial ingredient(s) 63 to be fed in liquid state or solution form,is enclosed within a non-permeable coating 64 that is surrounded by alayer 65 of hydro-active material that is entirely confined within anouter semi-permeable membrane coating 66. Osmotic pressure developing inthe hydro-active layer 65 upon infusion of moisture thereinto compressesthe core 67 containing the liquid form beneficial ingredient(s) 63 andforces that liquid out steadily through a very small passageway 68 fromthe core 67 to the exterior of the reservoir.

Turning now to FIG. 8A, the controlled release dosage form unit as shownin either of FIGS. 7 and 8 may be coated with a readily soluble coating,such as coating 69, which may be a coating of marker dye or beneficialagent for the purpose of getting a quick initial release of such dye orbeneficial agent. In the case of a beneficial agent such as amedicament, this may be desirable in order to get a blood content levelup quickly, after which a steady sustained release level may be needed.

The controlled release reservoir 70 depicted in FIG. 9 is of the type inwhich there is provided, within a carrier envelope 71 that is veryquickly soluble or disintegrable in the medium of the liquid enteralnutritional product, a quantity of microcapsules or molecular sievingtype particles 72. If microcapsules, the particles 72 are microsphereseach individually coated and each containing the same beneficialingredient or mixture thereof, with a plurality of distinct numericalportions or fractions thereof each provided with a coating thatdissolves or disintegrates in or is permeated by the medium of theliquid enteral nutritional product. The various numerical fractions,respectively, each have a coating of a different thickness whereby uponmaking a blend of the microcapsules with a fraction that is uncoated,the mixture shows a sustained release effect when exposed to an aqueousmedium, such as the medium of a liquid enteral nutritional product. Theenvelope and coatings must essentially be acceptable for nutritionalfeeding, or disintegrable, i.e., suspendable, but not necessarilysoluble.

If the particles 72 are of a molecular sieving type, or a mixture of twoor more molecular sieving grades, the particles have been impregnatedwith a beneficial ingredient or ingredients to be supplied duringfeeding and the particles agglomerated into desired size granules orclumps that are usable with or without being coated, to form acontrolled release dosage form usable according to the invention, thecoating, if applied, being soluble, or disintegrable, i.e., suspendable,in or permeable to the medium of the liquid enteral nutritional productto be modified. The molecular sieving type material has a porousstructure with non-aligned pores where pore size is criticallycontrolled in manufacture in order to create the property of holdingmolecules of different size characteristics or molecular weights in aselective manner. The holding or storing properties impart sustainedrelease behavior.

The carrier for controlled release dosage form units may also take theform shown in FIG. 9 but containing a fibrous material in which thefibers are hollow and permeable and slowly release substances such asthe beneficial ingredients herein added to a nutritional product. Ameasured quantity of such fibers, in a coil or in chopped form, may beused in a retaining means such as a sleeve or bag, or agglomerated witha binder, or coated with a dispersible, disintegrable or permeablecoating. Such fibers, which may be formed primarily of a cellulose etheror ester, are capable of storing up and subsequently yielding up abeneficial ingredient or mixture of ingredients, upon contact withflowing liquid enteral nutritional product within the drip chamber orother formulation chamber.

The fibrous and highly porous tea bag-type of carrier envelope 79 shownin FIG. 9A may also be used to hold or support, within a formulationchamber, a quantity of microencapsulated microspheres, or a quantity ofmolecular sieving type material or, for example, a quantity of choppedfine hollow permeable fibers 78, any of which forms holding orcontaining a dosage amount of one or more beneficial agents. Such a teabag-type of envelope, or a plurality thereof, may also be used toposition within a formulation chamber any combination of: (1) one ormore beneficial agents in controlled release dosage form; (2) one ormore beneficial agents in controlled dosage form along with one or morebeneficial agents not in controlled dosage form, wherein the beneficialagents not in controlled dosage form may be the same or different agentsthan those present in controlled dosage form; and (3) a marker dye ordye mixture in combination with either (1) or (2) and in a controlledrelease dosage form setting, as well as in any external coatings ofcontrolled release dosage form units. Wherein more than one formulationchamber is used, the additional formulation chamber may have positionedtherein, e.g., a fibrous carrier bag having therein only non-controlledbeneficial agent along with or without marker dye.

Any mode of making a sustained or controlled release storage coating,envelope or binder may be used in making a controlled release dosageform unit usable according to the invention so long as the soluble,dispersible or disintegrable components of the dosage form units usedare physiologically acceptable and the controlled release dosage formunit is capable of storing one or more beneficial ingredients as abovedefined until use and releasing the same into a liquid enteralnutritional product at a useful rate or manner and/or over a usefulperiod of time of at least one-half hour and preferably over at leasttwo hours during enteral feeding, or longer if needed for certainmedicaments and nutrients. Tablets and capsules and other dosage formsmay generally be coated with well known materials that slow down anddelay the solubilization or suspension of the beneficial agent,materials such as zein, shellac, methacrylate polymers and copolymers,and cellulose ethers and esters that are frequently used for thepurpose. Such materials are described in U.S. Pat. No. 5,160,742 and aregenerally adaptable for the present purpose, although the coatedarticles described in the patent are used in a different manner.

Wherein it is necessary or quite important to provide a beneficialingredient, or a mixture of ingredients, as herein defined, for example,one or more medicaments, according to the invention and at a fairlyuniform rate over time, with preferably not more than about a 25%variation above or below the median rate over a period of two to about24 hours or more, the osmotic pump and other osmotic delivery systemsare to be preferred. Generally, a wide range of rates is usable as longas at least an effective amount is supplied without reaching excessiveamounts.

Amongst the beneficial agents that are most likely to be added toconventional enteral nutritional compositions are, for example,nutrients, such as, glutamine, arginine, fermentable dietary fibers,non-fermentable dietary fibers, enzymes such as lipases, combinations ofamino acids, oligosaccharides such as fructo-oligosaccharides, vitamins,short chain (C₃ -C₄) fatty acids, pyruvate precursors in the form ofpyruvamide, or pyruvyl-amino acids, such as, pyruvylglycine,pyruvyl-alanine, pyruvyl-leucine, pyruvyl-valine, pyruvyl-sarcosamineand their amides, esters and salts, structured lipids, d-cyroinositol,lactoferrin, marine oils and acidulents such as ascorbic acid. Anexample of a structured lipid which provides excellent nutritionalsupport is a glycerol backbone with at least one gamma linolenic acid ordihomogamma-linolenic acid residue in combination with a medium chain(C₆ -C₁₂) fatty acid residue and a C₁₈ -C₂₂ n-3 fatty acid residueselected from alpha-linolenic and stearodonic, eicosapentaenoic anddocosahexaenoic acid.

Medicaments that may usefully administered in this manner include, forexample, antihistamine drugs; anti-infective agents, such asantibiotics, antivirals and urinary tract anti-infectives;antineoplastic agents; autonomic drugs such as adrenergic agents andskeletal muscle relaxants; blood formation and coagulation drugs;cardiovascular drugs; central nervous system agents; diagnostic agents;electrolytic, caloric and water balance agents; enzymes; antitussive,expectorant and mucolytic agents; gastrointestinal drugs such asantacids; gold compounds; hormones and synthetic substitutes; smoothmuscle relaxants; and unclassified therapeutic agents. Other examplesare H₂ blockers like Tagamet®, prokinetic medications, bioactivepeptides, medication for diabetic condition, chemotherapy agents, or anymedication intended for oral administration that will not reactadversely with the nutritional formulation being fed into thegastrointestinal tract.

Probiotics that may be usefully administered in this manner include, forexample, Lactobacillus acidophilus GG, as described in U.S. Pat.4,839,281, Lactobacillus reuteri, Lactobacillus animalis, andLactobacillus salivarius, as described in WO 93/02558. Probiotics arelive microorganisms that aid in the digestion of food or that helpcontrol the population of harmful microorganisms in the intestines.

If desired, a physiologically acceptable marker dye or dye mixture maybe provided in the formulation chamber or chambers in addition to one ormore of the beneficial ingredients above disclosed in order that theflow of modified liquid nutritional product may be made visible as anaid to the caregiver. This may be done by placing in the formulationchamber one or more sustained release dosage form units containing boththe dye or dye mixture and the beneficial ingredient(s), if such dosageform units are available. Or, a controlled release dosage form unitcontaining the dye or dye mixture and a separate controlled releasedosage form unit containing the beneficial ingredient(s) may be placedtogether in the formulation chamber. As indicated above, in order toimpart prompt visibility to the flow of modified nutritional product asan aid to the caregiver, it may be preferred to apply an external,readily soluble coating of the marker dye to a controlled release dosageform unit, ordinarily one containing marker dye. The marker dye isadmixed with a small amount of one or more conventional easilydispersible tablet coating excipients, such as, polyvinylpyrrolidinehaving an average molecular weight in the range of about 35,000 to50,000, mannitol, magnesium stearate, and zein or guar gum, in applyingthe dye to the dosage form unit during manufacture. Generally the amountof excipients in total is less than about 10 percent by weight of thecoating. Or, the dosage form unit may be simply dipped in a solution ofthe marker dye and dried.

A marker dye or dye mixture that is useful according to the invention isa colorant dye or a fluorescent dye or a mixture of such dyes that isphysiologically acceptable to the patient and compatible with thebeneficial agents being fed therewith. The dye or dye mixture must alsobe capable of being taken up in detectable concentration in the liquidmedium of the liquid enteral nutritional product while the product flowsthrough a drip chamber or other formulation chamber having positionedtherein at least one sustained release dosage form unit containing themarker dye or dyes. If the dye is detectable in the drip chamber, it canbe expected to be detectable, ordinarily, if it somehow reaches the oralcavity of the patient.

The marker dye employed may be a colorant dye that imparts color that isvisible under white light, for example, normal daylight or artificialroom light encountered in a hospital or clinic, or, the marker dye maybe a fluorescing dye that fluoresces visibly under ultraviolet light,or, a mixture of a colorant dye and a fluorescing dye. A mixture of acolorant dye and a fluorescing dye appears to be especially advantageousin that flow through the formulation chamber is readily perceived undernormal lighting conditions with colorant dye present, while even a smallamount of nutritional product out of place, for example, in the oralcavity or nasal passage, will be more easily detected with the aid ofultraviolet light if it contains a fluorescing dye. This is because ofthe nature of the fluorescing dyes that are especially visible underultraviolet light even when present in very low concentration.

The dye or dye mixture used must be physiologically acceptable. Usuallyfood grade colorant dyes approved under the provisions of the UnitedStates Food, Drug and Cosmetic Act are suitable. Preferred are F.D. & C.Blue #1 and F.D. a C. Blue #2 dyes. The dye or dye mixture used must besoluble in the medium of the liquid enteral nutritional product beingfed and compatible with the beneficial ingredient(s) being added duringthe feeding. Generally about 0.1 milligram of dye per milliliter ofliquid enteral nutritional product is desired to give a readily visiblecoloration to the nutritional product.

Wherein it is important to be able to detect misdirected liquid enteralnutritional product, the marker dye used may be a fluorescing dye, suchas F.D.& C. Red #3, which is highly visible at a very low concentrationunder ultraviolet light and also imparts a visible coloration to theliquid nutritional product under white light conditions. Other suitablefluorescing dyes are: quinine, F.D.& C. Red #22, F.D.& C. #28,fluorescein, and D 282 UV Blue available from DaGlo of Cincinnati, Ohioand also identified as 16470-24-9 in the Chemical Abstracts System witha color index of 220 as a fluorescent brightener. As indicated above, ifdesired, a mixture of colorant dye and fluorescing dye may be used.Generally, adding to the nutritional product in the formulation chamberabout 0.01 to 0.05 mg/ml of fluorescing dye is adequate fordetectability under ultraviolet light.

A feeding set, such as the kit 20 shown in FIG. 15, is convenientlyprovided in packaged form ready for use in feeding a liquid enteralnutritional product. The kit includes a Controlled release dosage formunit 32, a drip chamber 27 or other formulation chamber, and liquidcommunication means 28 consisting mainly of a length of flexible tubingattached at one end to the outlet of the drip chamber 27 and at theother end to a fitting 30 for coupling attachment to a feeding tube. Thefitting 30 is shown with a cap 55 telescoped for purposes ofillustration. The cap is simply for protection of the fitting 30 untilthe feeding set is used. The controlled release dosage form unit 32 hasalready been placed in the drip chamber 27 and contains one or morebeneficial ingredients as defined hereinabove for modification of aliquid enteral nutritional product during feeding thereof, andadditionally a marker dye, if desired. The kit may also be provided witha plurality of controlled release dosage form units 32 within the dripchamber 27 if a single dosage form unit does not contain each type ofbeneficial ingredient desired for modification of the nutritionalproduct or if it is desired to add a marker dye and it is not present inthe controlled release dosage form units for the beneficial ingredientsselected.

A similar kit 20c, as shown in FIG. 10, includes the controlled releasedosage form unit 32 which has not been placed in the drip chamber 27before shipping the kit, but accompanies the drip chamber as part of thekit. Other kits are prepared with various numbers and varieties ofcontrolled release dosage form units containing various beneficial agentand marker dye combinations and beneficial agents not in controlledrelease form, to accompany the feeding sets.

In a preferred embodiment of the apparatus of the invention of the typeillustrated in FIG. 2, a controlled release dosage form unit of the typeillustrated in FIG. 8A is positioned in the formulation chamber. Thedosage form unit contains glutamine and F.D.& C. Blue #1 dye and iscoated with a layer of the same blue dye admixed with about 3 percent byweight in total of polyvinylpyrrolidine having an average molecularweight in the range of about 35,000 to 44,500. The feeding kit isconnected to a hanging supply container of a liquid enteral nutritionalproduct having a viscosity of about 40 cps., such as PULMOCARE®, aproduct of the Ross Products Division of Abbott Laboratories, Columbus,Ohio, and a steady flow of the nutritional product is commenced. The dyecoating provides immediate visible color within the drip chamber within2 seconds and the controlled release dosage form unit provides the bluedye in a concentration of at least 0.075 mg/ml for a period of over1,440 minutes during the flow of about 3,000 ml of the liquid enteralnutritional product. The dosage form unit also provides glutamine at aconcentration of at least 1.25 mg/ml during the flow of the liquidenteral nutritional product, commencing after about 1 ml of flow.

We claim:
 1. An apparatus for modifying a liquid enteral nutritionalproduct during the feeding thereof comprising:a formulation chamber, theformulation chamber having an inlet and an outlet and the inletconnected to a container with a liquid enteral nutritional producthaving a viscosity in the range of about 5 to about 300 centipoises soas to receive said product therefrom, the formulation chamber furthercomprising at least one beneficial agent in at least one controlledrelease dosage form unit and the formulation chamber containing the atleast one controlled release dosage form unit, each beneficial agentbeing selected from the group consisting of nutrients, medicaments,probiotics and diagnostic agents that are each dispersed in said liquidenteral nutritional product, the controlled release dosage form unitbeing capable of delivering each beneficial agent into said liquidenteral nutritional product over a time period in the range of at leastabout 30 minutes during the feeding thereof to a patient.
 2. Theapparatus of claim 1 wherein the formulation chamber is a drip chamber.3. The apparatus of either claim 1 or claim 2 wherein the formulationchamber comprises additionally at least one beneficial agent not in acontrolled release dosage form.
 4. The apparatus of either claim 1 orclaim 2 wherein the formulation chamber comprises additionally at leastone marker dye in a controlled release dosage form unit, said controlledrelease dosage form unit being a means for providing and dispensingmarker dye into a liquid enteral nutritional product having a viscosityin the range of about 5 to about 300 centipoises when the controlledrelease dosage form unit is physically contacted thereby during thefeeding thereof to a patient over a time period of about 2 to about 24hours.
 5. The apparatus of claim 4 wherein the controlled release dosageform unit containing marker dye is coated with a quick release layer ofmarker dye.
 6. The apparatus of either claim 1 or claim 2 wherein theformulation chamber comprises additionally both a marker dye in acontrolled release dosage form unit and at least one beneficial agentnot in a controlled release dosage form unit, said controlled releasedosage form unit being a means for dispensing marker dye into a liquidenteral nutritional product having a viscosity in the range of about 5to about 300 centipoises when the controlled release dosage form unit isphysically contacted thereby during the feeding thereof to a patientover a time period of about 2 to about 24 hours.
 7. The apparatus ofclaim 2 wherein the drip chamber has in fluid connection to the outletthereof at least one formulation chamber, and at least one of the dripchamber and each such formulation chamber comprising at least onebeneficial agent in a controlled release dosage form unit and the otherchamber or chambers comprising at least one member of the groupconsisting of (a) beneficial agents in controlled release dosage formunits, (b) beneficial agents not in controlled release dosage form, and(c) marker dyes in controlled release dosage form units wherein saidcontrolled release dosage form is a means for dispensing marker dye intoa liquid enteral nutritional product having a viscosity in the range ofabout 5 to about 300 centipoises when the controlled release dosage formunit is physically contacted thereby during the feeding thereof to apatient over a time period of about 2 to about 24 hours.
 8. Theapparatus of claim 1 wherein the outlet of the formulation chamber isconnected to fluid communication means connectable to a feeding tubewhich communicates with the gastrointestinal tract of a patient.
 9. Theapparatus of claim 1 wherein the at least one beneficial agent isglutamine.
 10. The apparatus of claim 1 wherein the at least onebeneficial agent is a probiotic.
 11. The apparatus of claim 1 whereinthe at least one beneficial agent is a pyruvate precursor.
 12. Theapparatus of claim 1 wherein the at least one beneficial agent is astructured lipid.
 13. An apparatus for liquid enteral nutritionalproduct feeding comprising:a formulation chamber having an inlet and anoutlet and connected to a supply container with a liquid enteralnutritional product having a viscosity in the range of about 5 to 300centipoises so as to receive said product therefrom, the formulationchamber further comprising at least one beneficial agent in controlledrelease dosage form unit, each beneficial agent in controlled releasedosage form unit being disposed within the formulation chamber so as tobe wetted by or immersed in the liquid enteral nutritional producttraversing therethrough and each beneficial agent being selected fromthe group consisting of: nutrients, medicaments, probiotics anddiagnostic agents, and chemically and physiologically compatiblecombinations thereof, and, any of the foregoing beneficial agents orchemically and physiologically compatible combinations thereof togetherwith a physiologically acceptable marker dye, each beneficial agent andmarker dye disposed in the formulation chamber being dispersed in themedium of the liquid enteral nutritional product, the controlled releasedosage form unit being capable of delivering each beneficial agent intosaid liquid enteral nutritional product over a time period of at leastabout 30 minutes; and fluid communication means capable of operativelyconnecting the outlet of the drip chamber to a tube for feeding, intothe gastrointestinal tract of a patient, the modified liquid enteralnutritional product.
 14. The apparatus of claim 13 wherein theformulation chamber is a drip chamber.
 15. The apparatus of claim 13wherein the formulation chamber comprises a plurality of controlledrelease dosage form units each containing the same or different at leastone beneficial agent.
 16. The apparatus of claim 13 for use indelivering an aqueous liquid enteral nutritional product, wherein saidat least one beneficial agent is water soluble or dispersible and thecontrolled release dosage form unit is a water soluble or dispersibleingredient delivery device containing said at least one water soluble ordispersible beneficial agent, the device comprising;at least one innermass transfer conductor; the at least one water soluble or dispersiblebeneficial agent being present in a physiologically useful ordiagnostically detectable amount, with the at least one water soluble ordispersible beneficial agent disposed in the at least one inner masstransfer conductor, the at least one inner mass transfer conductor beingpermeable to the passage of the at least one water soluble ordispersible beneficial agent; and a membrane surrounding the at leastone inner mass transfer conductor, which membrane releases at least auseful amount of the at least one water soluble or dispersiblebeneficial agent into the liquid enteral nutritional product employedwhen the product is gradually passed over the membrane and administeredenterally to a patient.
 17. The apparatus of claim 13 for use indelivering an aqueous liquid enteral nutritional product, wherein saidat least one beneficial agent is water soluble or dispersible and thecontrolled release dosage form unit is an osmotically driven device, thedevice comprising:a capsule formed by an exterior wall made up, at leastin part, by a semipermeable composition that maintains its integrity inthe presence of an aqueous fluid, the exterior wall surrounding ahydro-activated layer comprising a hydro-activated swellable compositionor a hydro-activated composition that occupies space at a controlledrate, and an inner capsule surrounded by the hydro-activated layer andcommunicating with a lumen extending to the exterior of the outercapsule, the inner capsule containing at least a useful amount of the atleast one water soluble or dispersible beneficial agent in liquidformulation form and the wall of the inner capsule being substantiallynon-permeable to the liquid enteral nutritional product.
 18. Theapparatus of claim 13 wherein the controlled release dosage form unit isa particulate controlled release composition comprisingmicroencapsulated particles containing at least a useful amount of theat least one beneficial agent, the particles having a plurality ofcoating thicknesses that gradually dissolve or disintegrate and releasethe at least one beneficial agent within the particle when contactedover time by the liquid enteral nutritional product.
 19. The apparatusof claim 13 wherein the controlled release dosage form unit is amolecular sieving type dosage form impregnated with at least a usefulamount of the at least one beneficial agent, the molecular sievingdosage form gradually yielding up the at least one beneficial agent tothe medium of the liquid enteral nutritional product when contacted overtime by the liquid enteral nutritional product.
 20. The apparatus ofclaim 13 wherein the controlled release dosage form unit contains as thebeneficial agent at least one nutrient selected from the groupconsisting of glutamine, vitamins arginine, oligosaccharides, shortchain fatty acids, enzymes, fermentable dietary fibers, non-fermentabledietary fibers, pyruvamide, pyruvyl-amino acids and their amides, estersand salts, structured lipids, d-cyroinositol, lactoferrin, marine oilsand acidulants.
 21. The apparatus of claim 20 wherein the controlledrelease dosage form unit contains as the beneficial agent at least onenutrient selected from the group consisting of glutamine, ascorbic acidand a pyruvate.
 22. The apparatus of claim 13 wherein the controlledrelease dosage form unit contains as the beneficial agent at least onemedicament selected from the group consisting of antacids, antibiotics,probiotic medications, prokinetic medications, bioactive peptides,medication for diabetic condition, chemotherapy agents, and any othermedication intended for oral administration that will not reactadversely with the nutritional formulation being fed into thegastrointestinal tract.
 23. The apparatus of claim 13 wherein thecontrolled release dosage form unit contains as the beneficial agent aprobiotic selected from the group consisting of Lactobacillus reuteriLactobacillus acidophilus, Lactobacillus animalis and Lactobacillussalivarius.
 24. The apparatus of claim 13 wherein the formulationchamber contains at least one beneficial agent selected from the groupconsisting of a marker dye in a controlled release dosage form unit anda beneficial agent not in controlled release dosage form unit inaddition to the controlled release dosage form unit containingbeneficial agent.
 25. The apparatus of claim 13 wherein each controlledrelease dosage form unit contains a physiologically acceptable markerdye in addition to the at least one beneficial agent.
 26. The apparatusof claim 13 wherein the controlled release dosage form unit is providedwith an exterior layer that substantially maintains its integrity for atleast the useful life of the dosage form unit during a feeding whileexposed to liquid enteral nutritional composition, and the dosage formunit is in the shape of a rectangular solid.
 27. The apparatus of claim13 wherein the controlled release dosage form unit is confined within amesh bag within the drip chamber.
 28. The apparatus of claim 13 whereinthe controlled release dosage form unit is confined within a foraminousbag within the drip chamber.
 29. The apparatus of claim 13 wherein thefluid communication means includes a flexible tubing section suitablefor use with a pump.
 30. The apparatus of claim 13 wherein the dripchamber contains a plurality of controlled release dosage form units.31. The apparatus of claim 13 wherein the fluid communication meansincludes additionally as a component thereof at least one additionalformulation chamber having therein at least one controlled releasedosage form unit containing the same or different at least onebeneficial agent.
 32. The apparatus of claim 31 wherein at least one ofthe drip chamber and at least one additional formulation chambercontains a plurality of controlled release dosage form units containingat least one beneficial agent.
 33. The apparatus of claim 31 wherein theat least one additional formulation chamber contains a controlledrelease dosage form unit containing only a physiologically acceptablemarker dye.
 34. A drip chamber adapted for use as part of an enteralfeeding set, the drip chamber comprising a sustained release dosage formunit, and a liquid enteral nutritional product having a viscosity in therange of about 5 to about 30 centipoises, the sustained release dosageform unit being disposed within the drip chamber and containing at leasta useful amount of at least one beneficial agent for modification ofsaid liquid enteral nutritional product during feeding, the beneficialagent being selected from the group consisting of nutrients,medicaments, probiotics and diagnostic agents, and chemically andphysiologically compatible combinations thereof, and any of theforegoing beneficial agents or combinations of beneficial agentstogether with a physiologically acceptable marker dye or mixture ofdyes, the controlled release dosage form unit being a means ofdelivering each beneficial agent into said liquid enteral nutritionalproduct over a time period of at least about 30 minutes.
 35. The dripchamber of claim 34 having disposed therein at least one additionalsustained release dosage form unit, each unit containing at least auseful amount of at least one of the beneficial agents.
 36. A kit forfeeding liquid enteral nutritional product into the gastrointestinaltract of a patient, comprising:a formulation chamber having an inlet andan outlet and connected to a supply container with a liquid enteralnutritional product having a viscosity in the range of about 5 to about300 centipoises so as to receive said product therefrom; the formulationchamber further comprising at least one controlled release dosage formunit containing at least one beneficial agent and up to a plurality ofmarker dyes, each at least one controlled release dosage form unit beingdisposed within the formulation chamber so as to be wetted by orimmersed in said liquid enteral nutritional product within saidformulation chamber; and fluid communication means having first andsecond ends, the first end being operatively connected to the outlet ofthe formulation chamber and the second end being capable of beingoperatively connected to a tube for feeding a liquid enteral nutritionalproduct into the gastrointestinal tract of a patient, each controlledrelease dosage form unit being a means of delivering each beneficialagent into said liquid enteral nutritional product over a time period ofat least about 30 minutes.
 37. A kit for feeding liquid enteralnutritional product into the gastrointestinal tract of a patient,comprising:a formulation chamber having an inlet and an outlet andconnected to a supply container with a liquid enteral nutritionalproduct having a viscosity in the range of about 5 to about 300centipoises so as to receive said product therefrom; at least onecontrolled release dosage form unit containing at least one beneficialagent and up to a plurality of marker dyes, each at least one controlledrelease dosage form unit accompanying the formulation chamber and beingoutside thereof; and fluid communication means having first and secondends, the first end being operatively connected to the outlet of theformulation chamber and the second end being capable of beingoperatively connected to a tube for feeding a liquid enteral nutritionalproduct into the gastrointestinal tract of a patient, each controlledrelease dosage form unit being capable of delivering each beneficialagent into said liquid enteral nutritional product over a time period ofat least about 30 minutes.